Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be
causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within
these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association
(GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a
method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single
nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed
using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The
association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined
functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence
from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation.
An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups
related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004),
thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma
susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an
association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and
heterogeneity may present challenges.